title: DLG1/SAP97 modulates transforming growth factor alpha bioavailability.
abstract: TGFalpha and its receptor EGFR participate in the development of a wide range of tumors including gliomas, the main adult primary brain tumors. TGFalpha soluble form results from the cleavage by the metalloprotease TACE/ADAM17 of the extracellular part of its transmembrane precursor, pro-TGFalpha. To gain insights into the mechanisms underlying TGFalpha bioavailability, a yeast two-hybrid screen was performed to identify proteins interacting with pro-TGFalpha intracellular domain (ICD). DLG1/SAP97 (Discs Large Gene 1 or Synapse Associated Protein 97) was found to interact with both pro-TGFalpha and TACE ICDs through distinct PDZ domains. An in vivo pro-TGFalpha-DLG1-TACE complex was detected in U251 glioma cells and in gliomas-derived tumor initiating cells. Interaction between DLG1 and TACE diminished in response to stimulations promoting pro-TGFalpha shedding. Manipulation of DLG1 levels revealed dual actions of DLG1 on pro-TGFalpha shedding, favoring approximation of pro-TGFalpha and TACE, while limiting TACE full shedding activity. These results show that DLG1 participates in the control of TGFalpha bioavailability through its dynamic interaction with the growth factor precursor and TACE.
authors.affiliation: Inserm, UMR894, University of Paris 5, 75014 Paris, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Surena
authors.forename: Giselle P
authors.initials: GP
authors.lastname: de Faria
authors.forename: Jeanne-Marie
authors.initials: JM
authors.lastname: Studler
authors.forename: Franck
authors.initials: F
authors.lastname: Peiretti
authors.forename: Morgane
authors.initials: M
authors.lastname: Pidoux
authors.forename: Jacques
authors.initials: J
authors.lastname: Camonis
authors.forename: Hervé
authors.initials: H
authors.lastname: Chneiweiss
authors.forename: Etienne
authors.initials: E
authors.lastname: Formstecher
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Junier
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry / Q000378:metabolism; D000072198:ADAM17 Protein; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D000074288:Discs Large Homolog 1 Protein; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism*; D011485:Protein Binding; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000737:chemistry / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; D008565:Membrane Proteins; D011498:Protein Precursors; D016211:Transforming Growth Factor alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human